Project Summary/Abstract Short-term fasting has been shown to provide host protective effects from the toxicity associated with high- dose chemotherapy. We found a novel protective effect conferred by short-term fasting when treating mice with high dose chemotherapy. We demonstrated that fasting mice for 24 h confers protection to small intestinal (SI) stem cells from high-dose etoposide. We also showed increased survival in mice that have been fasted for 24 h prior to treatment with toxic doses of radiation. We will test the hypothesis that the metabolic changes associated with fasting lead to epigenetic changes in SI stem cells, which in turn, leads to expression of genes whose protein products protect SI stem cells from lethal DNA damage. This hypothesis will be tested in fasted mice exposed to high-dose etoposide and mice exposed to high-dose radiation. The clinical applications of our findings will be evaluated in a mouse model of pancreatic cancer.